Search

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma (CTCL). While MF generally follows an indolent course, a subset of patients will experience progressive and/or treatment-refractory disease; Sézary syndrome is an aggressive lymphoma associated with high morbidity and mortality. Although allogeneic hematopoietic cell transplant (allo-HCT) is the only currently available potentially curative treatment modality for MF/SS there is no published guidance on referral criteria, transplant timing orallo-HCT approach. To develop consensus clinical practice recommendations, we performed a Delphi survey of 32 specialists in dermatology (n = 9), transplant hematology/oncology (n = 10), non-transplant hematology/oncology (n = 8), and radiation oncology (n = 5) from across the United States. Consensus required agreement of ≥75% of participants. Sixteen consensus statements were generated on four topics: (1) criteria for referral for consideration for allo-HCT, (2) allo-HCT preparative regimens and procedures (3) disease status at the time of allo-HCT, and (4) multidisciplinary management in the pre- and post-transplant settings. These clinical practice guidelines provide a framework for decision-making regarding allo-HCT for MF/SS and highlight areas for future prospective investigation., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The present study outlines the development and initial validation of a conditional reasoning test for risk and incident propensity (CRT-RIP). Individuals carry with them a wide array of experiences, attitudes, and dispositions that may influence their proneness for risk-taking and incident involvement. Yet, measuring risk propensity has proven challenging due to the high levels of transparency found in the self-report measures that are presently available. We initially developed 28 conditional reasoning items to measure risk and incident propensity. With four developmental samples, we evaluated item characteristics. After applying item decision guidelines for conditional reasoning tests, we retained 14 items. Using three test samples and with the 14-item CRT-RIP, we assessed predictive and incremental validity over five-factor personality traits and an explicit, self-report measure of risk propensity. With one final sample, we provided further validation of the 14-item CRT-RIP. Findings demonstrate initial success in predicting various safety behaviors and outcomes. Ability to measure risk propensity and to predict safety behaviors is valuable because of the profound consequences that may proceed failure to enact safety behaviors including property damage, injury, illness, or even death. We discuss potential applications and suggest directions for future research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Competing Interests: None disclosed.

The purpose of this study is to examine the boundary conditions of transformational leadership, follower psychological capital, and their effects on follower mental health outcomes. Specifically, we utilize archival, multi-wave data from a military sample to examine whether the negative relationship between transformational leadership and adverse follower stress outcomes increases as the context shifts from a relatively safe environment to one in which follower lives are at risk. Additionally, psychological capital, a constellation of personal psychological resources, is also assessed to account for individual buffers against extreme stressors. Findings from the current study suggest that the negative relationship between transformational leadership and follower stress increases significantly when the context shifts to a high-risk, mortality-salient environment.

Competing Interests: Conflicts of interest None disclosed.

Cutaneous T-cell lymphoma (CTCL) is a chronic form of skin cancer. Skin-directed therapies rarely achieve complete clearance of lesions, and recurrences are frequent. In this case series, 9 patients with stage IA to IVA2 CTCL received intralesional (IL) therapy with 5-fluorouracil (5-FU) and imiquimod (IMQ) cream 5% daily to recalcitrant plaques and tumors. All 9 patients attained a complete response (CR) with no recurrences reported and no severe side effects. We find that combination IL 5-FU and IMQ cream 5% daily is a well-tolerated, effective, and durable skin-directed therapy for recalcitrant plaques and tumors in CTCL.

Importance: Given that mycosis fungoides-cutaneous T-cell lymphoma (MF/CTCL) is chronic, there is a need for additional therapies with minimal short- and long-term adverse effects. Topical synthetic hypericin ointment, 0.25%, activated with visible light is a novel, nonmutagenic photodynamic therapy (PDT)., Objectives: To determine the efficacy and safety of topical synthetic hypericin ointment, 0.25%, activated with visible light as a nonmutagenic PDT in early-stage MF/CTCL., Design, Settings, and Participants: This was a multicenter, placebo-controlled, double-blinded, phase 3 randomized clinical trial (FLASH study) conducted from December 2015 to November 2020 at 39 academic and community-based US medical centers. Participants were adults (≥18 years) with early-stage (IA-IIA) MF/CTCL., Interventions: In cycle 1, patients were randomized 2:1 to receive hypericin or placebo to 3 index lesions twice weekly for 6 weeks. In cycle 2, all patients received the active drug for 6 weeks to index lesions. In cycle 3 (optional), both index and additional lesions received active drug for 6 weeks., Main Outcomes and Measures: The primary end point was index lesion response rate (ILRR), defined as 50% or greater improvement in modified Composite Assessment of Index Lesion Severity (mCAILS) score from baseline after 6 weeks of therapy for cycle 1. For cycles 2 and 3, open label response rates were secondary end points. Adverse events (AEs) were assessed at each treatment visit, after each cycle, and then monthly for 6 months. Data analyses were performed on December 21, 2020., Results: The study population comprised 169 patients (mean [SD] age, 58.4 [16.0] years; 96 [57.8%] men; 120 [72.3%] White individuals) with early-stage MF/CTCL. After 6 weeks of treatment, hypericin PDT was more effective than placebo (cycle 1 ILRR, 16% vs 4%; P = .04). The ILRR increased to 40% in patients who received 2 cycles of hypericin PDT (P < .001 vs cycle 1 hypericin) and to 49% after 3 cycles (P < .001 vs cycle 1 hypericin). Significant clinical responses were observed in both patch and plaque type lesions and were similar regardless of age, sex, race, stage IA vs IB, time since diagnosis, and number of prior therapies. The most common treatment-related AEs were mild local skin (13.5%-17.3% across cycles 1-3 vs 10.5% for placebo in cycle 1) and application-site reactions (3.2%-6.9% across cycles 1-3 vs 4% for placebo in cycle 1). No drug-related serious AEs occurred., Conclusion and Relevance: The findings of this randomized clinical trial indicate that synthetic hypericin PDT is effective in early-stage patch and plaque MF/CTCL and has a favorable safety profile., Trial Registration: ClinicalTrials.gov Identifier: NCT02448381.

Competing Interests: None disclosed.

Background: Intravenous TTI-621 (SIRPα-IgG1 Fc) was previously shown to have activity in relapsed or refractory haematological malignancies. This phase 1 study evaluated the safety and activity of TTI-621 in patients with percutaneously accessible relapsed or refractory mycosis fungoides, Sézary syndrome, or solid tumours. Here we report the clinical and translational results among patients with mycosis fungoides or Sézary syndrome., Methods: This multicentre, open-label, phase 1 study was conducted at five academic health-care and research centres in the USA. Eligible patients were aged 18 years or older; had injectable, histologically or cytologically confirmed relapsed or refractory cutaneous T-cell lymphoma (CTCL) or solid tumours; Eastern Cooperative Oncology Group performance status of 2 or less; and adequate haematological, renal, hepatic, and cardiac function. TTI-621 was injected intralesionally in a sequential dose escalation (cohorts 1-5; single 1 mg, 3 mg, or 10 mg injection or three 10 mg injections weekly for 1 or 2 weeks) and in expansion cohorts (cohorts 6-9; 2 week induction at the maximum tolerated dose; weekly continuation was allowed). In cohort 6, patients were injected with TTI-621 in a single lesion and in cohort 7, they were injected in multiple lesions. In cohort 8, TTI-621 was combined with pembrolizumab 200 mg injections per product labels. In cohort 9, TTI-621 was combined with the standard labelled dose of subcutaneous pegylated interferon alpha-2a 90 μg. The primary endpoint was the incidence and severity of adverse events. The study is registered with ClinicalTrials.gov, NCT02890368, and was closed by the sponsor to focus on intravenous studies with TTI-621., Findings: Between Jan 30, 2017, and March 31, 2020, 66 patients with mycosis fungoides, Sézary syndrome, other CTCL, or solid tumours were screened, 35 of whom with mycosis fungoides or Sézary syndrome were enrolled and received intralesional TTI-621 (escalation, n=13; expansion, n=22). No dose-limiting toxicities occurred; the maximum tolerated dose was not established. In the dose expansion cohorts, the maximally assessed regimen (10 mg thrice weekly for 2 weeks) was used. 25 (71%) patients had treatment-related adverse events; the most common (occurring in ≥10% of patients) were chills (in ten [29%] patients), injection site pain (nine [26%]), and fatigue (eight [23%]). No treatment-related adverse events were grade 3 or more or serious. There were no treatment-related deaths. Rapid responses (median 45 days, IQR 17-66) occurred independently of disease stage or injection frequency. 26 (90%) of 29 evaluable patients had decreased Composite Assessment of Index Lesion Severity (CAILS) scores; ten (34%) had a decrease in CAILS score of 50% or more (CAILS response). CAILS score reductions occurred in adjacent non-injected lesions in eight (80%) of ten patients with paired assessments and in distal non-injected lesions in one additional patient., Interpretation: Intralesional TTI-621 was well tolerated and had activity in adjacent or distal non-injected lesions in patients with relapsed or refractory mycosis fungoides or Sézary syndrome, suggesting it has systemic and locoregional abscopal effects and potential as an immunotherapy for these conditions., Funding: Trillium Therapeutics., Competing Interests: Declaration of interests CQ reports research grants from Celgene; is a clinical investigator for Trillium Therapeutics, MiRagen, Bioniz, and Kyowa Kirin; and reports participation in advisory boards for Helsinn, miRagen, Bioniz, Trillium Therapeutics, and Kyowa Kirin. JAT reports research grants from Merck, Hoffmann-LaRoche, Pfizer, Five Prime, Novartis, Incyte, Trillium Therapeutics, and Xencor; and participation in advisory boards for Neoleukin, AVEO Oncology, and Regeneron. MHT reports research funding to their institution from Bristol Myers Squibb, Merck, Pharmacyclics, AstraZeneca, Eisai, Incyte, EMD Serono, Novartis, Seattle Genetics, AbbVie, Genentech, Eli Lilly, Roche, Acerta Pharma, Genzyme Corporation, and Pfizer; consulting or participation in advisory boards for Bristol Myers Squibb, Eisai, Novartis, Bayer, Sanofi/Genzyme, Array BioPharma, LOXO oncology, Blueprint Medicines, and Arqule; and participation in speakers' bureaus for Bristol Myers Squibb and Eisai. JAD reports speaker fees from Helsinn; and consultant fees from Regeneron. JMZ reports participation in advisory boards for Kyowa Kirin, Secura Bio, Mudi Pharma, Seattle Genetics, Legend Bio tech, and Ono Pharma; and research funding to their institution from Seattle Genetics, AbbVie, Karyopharm, and CRSPR. ARS has been a consultant for Acrotech, Bristol Myers Squibb-Celgene, Kyowa-Hakko-Kirin, and Portolla. SM has been a sub-investigator for Trillium Therapeutics, Bioniz, Kyowa Kirin, Affimed, Galderma, Soligenix, Helsinn, and Eisai; and been on the nurse advisory board for Kyowa Kirin. GHYL, PSP, RAU, NM, and YS report employment by and stock ownership in Trillium Therapeutics. OEA reports research grants from Trillium Therapeutics, Pfizer, and Kyowa Kirin; has been a clinical investigator for Trillium Therapeutics, Bioniz, Kyowa Kirin, Affimed, Galderma, Soligenix, Helsinn, and Eisai; and reports participation in advisory boards for Bioniz, Trillium Therapeutics, Kyowa Kirin, Medivir, and Almirall. CJ declares no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Importance: There is a paucity of evidence to guide physicians regarding prevention strategies for cutaneous squamous cell carcinoma (CSCC) in solid organ transplant recipients (SOTRs)., Objective: To examine the development and results of a Delphi process initiated to identify consensus-based medical management recommendations for prevention of CSCC in SOTRs., Evidence Review: Dermatologists with more than 5 years' experience treating SOTRs were invited to participate. A novel actinic damage and skin cancer index (AD-SCI), consisting of 6 ordinal stages corresponding to an increasing burden of actinic damage and CSCC, was used to guide survey design. Three sequential web-based surveys were administered from January 1, 2019, to December 31, 2020. Pursuant to Delphi principles, respondents thoroughly reviewed all peer responses between rounds. Supplemental questions were also asked to better understand panelists' rationale for their responses., Findings: The Delphi panel comprised 48 dermatologists. Respondents represented 13 countries, with 27 (56%) from the US. Twenty-nine respondents (60%) were Mohs surgeons. Consensus was reached with 80% or higher concordance among respondents when presented with a statement, question, or management strategy pertaining to prevention of CSCC in SOTRs. A near-consensus category of 70% to less than 80% concordance was also defined. The AD-SCI stage-based recommendations were established if consensus or near-consensus was achieved. The panel was able to make recommendations for 5 of 6 AD-SCI stages. Key recommendations include the following: cryotherapy for scattered actinic keratosis (AK); field therapy for AK when grouped in 1 anatomical area, unless AKs are thick in which case field therapy and cryotherapy were recommended; combination lesion directed and field therapy with fluorouracil for field cancerized skin; and initiation of acitretin therapy and discussion of immunosuppression reduction or modification for patients who develop multiple skin cancers at a high rate (10 CSCCs per year) or develop high-risk CSCC (defined by a tumor with approximately ≥20% risk of nodal metastasis). No consensus recommendation was achieved for SOTRs with a first low risk CSCC., Conclusions and Relevance: Physicians may consider implementation of panel recommendations for prevention of CSCC in SOTRs while awaiting high-level-of-evidence data. Additional clinical trials are needed in areas where consensus was not reached.

Background: Switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF)-containing antiretroviral therapy (ART) can improve renal function and bone mineral density in people with human immunodeficiency virus (PWH). The switch can also negatively influence cholesterol, but changes in body mass index (BMI) and atherosclerotic cardiovascular disease (ASCVD) risk are unknown., Methods: This retrospective observational study evaluated BMI and ASCVD risk score changes in virologically suppressed PWH who switched from TDF to TAF without switching other ART regimen components. Adults on TDF for ≥1 year with 2 consecutive HIV ribonucleic acid values <200 copies/mL before a TAF switch were included. Body weight, BMI, cholesterol, and ASCVD risk score were collected for the year before and after the switch. Pre- and postswitch values were compared with the Wilcoxon signed-rank test. Changes in BMI and ASCVD scores were modeled using generalized estimating equations regression., Results: One hundred ten patients were included. In unadjusted analyses, there were significant increases in weight, BMI, total cholesterol, LDL, HDL, and ASCVD risk score in the year after switching from TDF to TAF (each P ≤ .01). In regression models, switching from TDF to TAF was associated with a 0.45 kg/m 2 increase in BMI (95% confidence interval [CI], 0.14-0.76) and a 13% increase in ASCVD risk score (95% CI, 4%-23%)., Conclusions: We observed significant BMI and ASCVD score increases in PWH 1 year after switching from TDF to TAF. The mechanism of changes is unclear and requires additional study., (© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

This article introduces a new measure of resilience and five related protective factors. The Five-by-Five Resilience Scale (5×5RS) is developed on the basis of theoretical and empirical considerations. Two samples ( N = 475 and N = 613) are used to assess the factor structure, reliability, convergent validity, and criterion-related validity of the 5×5RS. Confirmatory factor analysis supports a bifactor model. The 5×5RS demonstrates adequate internal consistency as evidenced by Cronbach's alpha and empirical reliability estimates. The 5×5RS correlates positively with the Connor-Davidson Resilience Scale (CD-RISC), a commonly used measure of resilience. The 5×5RS exhibits similar criterion-related validity to the CD-RISC as evidenced by positive correlations with satisfaction with life, meaning in life, and secure attachment style as well as negative correlations with rumination and anxious or avoidant attachment styles. 5×5RS scores are positively correlated with healthy behaviors such as exercise and negatively correlated with sleep difficulty and symptomology of anxiety and depression. The 5×5RS incrementally explains variance in some criteria above and beyond the CD-RISC. Item responses are modeled using the graded response model. Information estimates demonstrate the ability of the 5×5RS to assess individuals within at least one standard deviation of the mean on relevant latent traits.

The mastocytoses comprise a group of proliferative stem cell disorders defined by the abnormal accumulation of mast cells (MCs) in the skin or other body tissues including the bone marrow, gastrointestinal tract, and liver. Systemic mastocytosis is defined by the presence of one major and one minor criterion or 3 minor criteria delineated by the World Health Organization (WHO). We present the case of a 57-year-old woman with a 10-year history of red-brown pruritic maculopapular lesions on the upper and lower extremities and trunk who was originally diagnosed with cutaneous mastocytosis. Symptoms had been adequately controlled with a combination of topical corticosteroids and antihistamines. After 9 years of controlled disease, the patient presented with increasingly severe breakthrough pruritus and new skin lesions on the head and neck. Further workup included bone marrow biopsy, which demonstrated dense mastocyte infiltrates without evidence of functional impairment, and elevated serum tryptase levels. Narrowband UVB (NB-UVB) phototherapy was initiated, and after 20 treatments the patient reported a marked decrease in symptoms. This case provides evidence of the efficacy of NB-UVB phototherapy in managing patients with long-standing indolent systemic mastocytosis (ISM) who have stopped responding adequately to topical corticosteroids and antihistamines.

During postnatal development rats demonstrate an age-dependent increase in NaCl chorda tympani (CT) responses and the number of functional apical amiloride-sensitive epithelial Na+ channels (ENaCs) in salt sensing fungiform (FF) taste receptor cells (TRCs). Currently, the intracellular signals that regulate the postnatal development of salt taste have not been identified. We investigated the effect of cAMP, a downstream signal for arginine vasopressin (AVP) action, on the postnatal development of NaCl responses in 19-23 day old rats. ENaC-dependent NaCl CT responses were monitored after lingual application of 8-chlorophenylthio-cAMP (8-CPT-cAMP) under open-circuit conditions and under ±60 mV lingual voltage clamp. Behavioral responses were tested using 2 bottle/24h NaCl preference tests. The effect of [deamino-Cys1, D-Arg8]-vasopressin (dDAVP, a specific V2R agonist) was investigated on ENaC subunit trafficking in rat FF TRCs and on cAMP generation in cultured adult human FF taste cells (HBO cells). Our results show that in 19-23 day old rats, the ENaC-dependent maximum NaCl CT response was a saturating sigmoidal function of 8-CPT-cAMP concentration. 8-CPT-cAMP increased the voltage-sensitivity of the NaCl CT response and the apical Na+ response conductance. Intravenous injections of dDAVP increased ENaC expression and γ-ENaC trafficking from cytosolic compartment to the apical compartment in rat FF TRCs. In HBO cells dDAVP increased intracellular cAMP and cAMP increased trafficking of γ- and δ-ENaC from cytosolic compartment to the apical compartment 10 min post-cAMP treatment. Control 19-23 day old rats were indifferent to NaCl, but showed clear preference for appetitive NaCl concentrations after 8-CPT-cAMP treatment. Relative to adult rats, 14 day old rats demonstrated significantly less V2R antibody binding in circumvallate TRCs. We conclude that an age-dependent increase in V2R expression produces an AVP-induced incremental increase in cAMP that modulates the postnatal increase in TRC ENaC and the neural and behavioral responses to NaCl., Competing Interests: The authors have declared that no competing interests exist.

The 24-item Abbreviated Character Strengths Test (ACST) was developed to efficiently measure character strengths (Peterson, Park, & Castro, 2011 ). However, its validity for this purpose has not yet been sufficiently established. Using confirmatory factor analysis to test a series of structural models, only a modified bifactor model showed reasonably acceptable fit. Further analyses of this model failed to demonstrate measurement invariance between male and female respondents. Relationships between ACST dimension and Big Five personality trait scores were generally weak-to-moderate, and support for hypotheses regarding each ACST virtue's expected correspondence with specific Big Five dimensions was mixed. Finally, scores on ACST dimensions accounted for a combined 12% of the variance in satisfaction with life scores, after controlling for socially desirability. Although an abbreviated measure of character strengths represents a practical need, considerable improvements to the ACST are needed for it to adequately meet this purpose.

Because of the structural and functional homology to the hair cells of the mammalian inner ear, the neurons that innervate the Drosophila external sense organs provide an excellent model system for the study of mechanosensation. This protocol describes a simple touch behavior in fruit flies which can be used to identify mutations that interfere with mechanosensation. The tactile stimulation of a macrochaete bristle on the thorax of flies elicits a grooming reflex from either the first or third leg. Mutations that interfere with mechanotransduction (such as NOMPC), or with other aspects of the reflex arc, can inhibit the grooming response. A traditional screen of adult behaviors would have missed mutants that have essential roles during development. Instead, this protocol combines the touch screen with mosaic analysis with a repressible cell marker (MARCM) to allow for only limited regions of homozygous mutant cells to be generated and marked by the expression of green fluorescent protein (GFP). By testing MARCM clones for abnormal behavioral responses, it is possible to screen a collection of lethal p-element mutations to search for new genes involved in mechanosensation that would have been missed by more traditional methods.

This manuscript uses item response theory (IRT) to estimate item characteristics of the Conditional Reasoning Test of Aggression (CRT-A). Using a sample size of 5,511 respondents, the present analysis provides an accurate assessment of the capability of the CRT-A to measure latent aggression. The one-parameter logistic (1PL) model, two-parameter logistic (2PL) model, and three-parameter logistic (3PL) model are compared before the item analysis. Results suggest that the 2PL model is the most appropriate dichotomous IRT model for describing the item characteristics of the CRT-A. Potential multdimensionality in the CRT-A is also examined. Results suggest that CRT-A items work as theoretically intended, with the probability of selecting an aggressive response increasing with latent trait levels. Information curves indicate that the CRT-A is best suited for use with individuals who are high on latent aggression. Exploratory analyses include an examination of polytomous IRT models and DIF comparing student and employee respondents. The results have implications for future research using the CRT-A as well as the identification of populations appropriate for measurement using this assessment tool., ((c) 2015 APA, all rights reserved).)

Modulatory effects of pHi and [Ca(2+)]i on taste receptor cell (TRC) epithelial sodium channel (ENaC) were investigated by monitoring chorda tympani (CT) responses to NaCl and KCl at various lingual voltages, before and after lingual application of ionomycin and with 0-10mM CaCl2 in the stimulus and rinse solutions adjusted to pHo 2.0-9.7. 0.1 and 0.5M KCl responses varied continuously with voltage and were fitted to an apical ion channel kinetic model using the same parameters. ENaC-dependent NaCl CT response was fitted to the same channel model but with parameters characteristic of ENaC. A graded increase in TRC [Ca(2+)]i decreased the ENaC-dependent NaCl CT response, and inhibited and ultimately eliminated its pH sensitivity. CT responses to KCl were pHi- and [Ca(2+)]i-independent. Between ±60 mV applied lingual potential, the data were well described by a linear approximation to the nonlinear channel equation and yielded 2 parameters, the open-circuit response and the negative of the slope of the line in the CT response versus voltage plot, designated the response conductance. The ENaC-dependent NaCl CT response conductance was a linear function of the open-circuit response for all pHi-[Ca(2+)]i combinations examined. Analysis of these data shows that pHi and [Ca(2+)]i regulate TRC ENaC exclusively through modulation of the maximum CT response., (© The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Nicotine elicits bitter taste by activating TRPM5-dependent and TRPM5-independent but neuronal nAChR-dependent pathways. The nAChRs represent common targets at which acetylcholine, nicotine and ethanol functionally interact in the central nervous system. Here, we investigated if the nAChRs also represent a common pathway through which the bitter taste of nicotine, ethanol and acetylcholine is transduced. To this end, chorda tympani (CT) taste nerve responses were monitored in rats, wild-type mice and TRPM5 knockout (KO) mice following lingual stimulation with nicotine free base, ethanol, and acetylcholine, in the absence and presence of nAChR agonists and antagonists. The nAChR modulators: mecamylamine, dihydro-β-erythroidine, and CP-601932 (a partial agonist of the α3β4* nAChR), inhibited CT responses to nicotine, ethanol, and acetylcholine. CT responses to nicotine and ethanol were also inhibited by topical lingual application of 8-chlorophenylthio (CPT)-cAMP and loading taste cells with [Ca2+]i by topical lingual application of ionomycin + CaCl2. In contrast, CT responses to nicotine were enhanced when TRC [Ca2+]i was reduced by topical lingual application of BAPTA-AM. In patch-clamp experiments, only a subset of isolated rat fungiform taste cells exposed to nicotine responded with an increase in mecamylamine-sensitive inward currents. We conclude that nAChRs expressed in a subset of taste cells serve as common receptors for the detection of the TRPM5-independent bitter taste of nicotine, acetylcholine and ethanol.

Purpose of Review: Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of skin-homing T-cell neoplasms, which represent approximately 75% of all primary cutaneous lymphomas. Currently available drug therapies, when effective, simply control disease and the only option for curing CTCL is stem cell transplant., Recent Findings: In the last year, there has been an incredible effort made to improve the understanding and treatment of CTCL. Recent findings indicate that epigenetic aberrations are integral to active disease. Furthermore, multiple tumor-derived immunological factors have also been shown to inhibit viability, proliferation, and cytokine production of nonmalignant T cells. Several novel targeted therapies show great potential, most promising being antibody drug conjugates targeting surface markers such as CD30 in some CTCL subtypes. Additional attractive targets involve the global modulation of epigenetic markers such as demethylation agents or HDAC inhibitors, either as single agents or in combination therapies., Summary: This is a concise review of recent advances in the field of CTCL with special focus on research articles over the preceding year.

Background: Primary cutaneous γ/δ T-cell lymphoma (PCGD-TCL) is aggressive and has a poor prognosis. In contrast, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) of the α/β T-cell receptor phenotype is known to follow an indolent course and have a more favourable prognosis. In the past, PCGD-TCL and SPTCL were often considered to be a manifestation of the same disease, and aggressive systemic polychemotherapy has commonly been the first-line therapy for both. Given the understanding that SPTCL is a separate and less aggressive entity, clinical data exclusively evaluating the efficacy of conservative treatment in SPTCL are needed., Objectives: To assess the overall clinical response to systemic corticosteroids in the treatment of SPTCL., Methods: This was a retrospective cross-sectional study based on a patient data repository from two tertiary care university hospitals in Zürich (Switzerland) and Tübingen (Germany). The repository spanned 13 years., Results: In four of the five patients (80%) with SPTCL, treatment with systemic corticosteroids induced a complete remission., Conclusions: Systemic corticosteroids may be an excellent first-line single-agent therapy for SPTCL., (© 2014 British Association of Dermatologists.)

The effects of small molecule ENaC activators N,N,N-trimethyl-2-((4-methyl-2-((4-methyl-1H-indol-3-yl)thio)pentanoyl)oxy)ethanaminium iodide (Compound 1) and N-(2-hydroxyethyl)-4-methyl-2-((4-methyl-1H-indol-3-yl)thio)pentanamide (Compound 2), were tested on the benzamil (Bz)-sensitive NaCl chorda tympani (CT) taste nerve response under open-circuit conditions and under ±60 mV applied lingual voltage-clamp, and compared with the effects of known physiological activators (8-CPT-cAMP, BAPTA-AM, and alkaline pH), and an inhibitor (ionomycin+Ca2+) of ENaC. The NaCl CT response was enhanced at -60 mV and suppressed at +60 mV. In every case the CT response (r) versus voltage (V) curve was linear. All ENaC activators increased the open-circuit response (ro) and the voltage sensitivity (κ, negative of the slope of the r versus V curve) and ionomycin+Ca2+ decreased ro and κ to zero. Compound 1 and Compound 2 expressed a sigmoidal-saturating function of concentration (0.25-1 mM) with a half-maximal response concentration (k) of 0.49 and 1.05 mM, respectively. Following treatment with 1 mM Compound 1, 8-CPT-cAMP, BAPTA-AM and pH 10.3, the Bz-sensitive NaCl CT response to 100 mM NaCl was enhanced and was equivalent to the Bz-sensitive CT response to 300 mM NaCl. Plots of κ versus ro in the absence and presence of the activators or the inhibitor were linear, suggesting that changes in the affinity of Na+ for ENaC under different conditions are fully compensated by changes in the apical membrane potential difference, and that the observed changes in the Bz-sensitive NaCl CT response arise exclusively from changes in the maximum CT response (rm). The results further suggest that the agonists enhance and ionomycin+Ca2+ decreases ENaC function by increasing or decreasing the rate of release of Na+ from its ENaC binding site to the receptor cell cytosol, respectively. Irrespective of agonist type, the Bz-sensitive NaCl CT response demonstrated a maximum response enhancement limit of about 75% over control value.

The first two integrase strand transfer inhibitors (INSTIs) approved for treatment of patients infected with human immunodeficiency virus (HIV) were raltegravir and elvitegravir. Both raltegravir and elvitegravir are now guideline-preferred agents as part of an antiretroviral regimen for treatment-naive patients. However, raltegravir is dosed twice/day. Elvitegravir is available in a single-tablet regimen and dosed once/day because it is administered with the pharmacokinetic booster cobicistat, a potent CYP3A4 inhibitor that can lead to clinically significant drug-drug interactions. In addition, raltegravir and elvitegravir have a low genetic barrier to resistance and are associated with cross-resistance. Dolutegravir is a new-generation INSTI administered once/day without a pharmacokinetic booster and can be coformulated in a single-tablet regimen. Phase III studies have demonstrated the efficacy and safety of dolutegravir for treatment-naive and treatment-experienced patients. Compared with other INSTIs, dolutegravir has a higher genetic barrier to resistance. Dolutegravir was approved by the U.S. Food and Drug Administration in August 2013 and joins raltegravir and elvitegravir as guideline-preferred agents for the management for HIV-infected treatment-naive patients., (© 2013 Pharmacotherapy Publications, Inc.)

Cerebral abscess caused by Candida spp. is a rare disease, with a nonspecific presentation, little data on treatment, and generally poor outcomes. We present a case of this type of Candida infection in a 57-year-old man with a history of uncontrolled diabetes mellitus and intravenous drug abuse, and review the literature on this disease. Our patient had a good treatment outcome with liposomal amphotericin B and flucytosine, followed by oral fluconazole. Comorbidities include prior antibiotic use (52%), prior surgery (28%), malignancy (28%), stem cell or solid organ transplant (20%), prior corticosteroid use (16%), central venous catheter (CVC) insertion (10%), and burns (7%). Diagnosis requires a high index of suspicion, as clinical presentations and laboratory data can be nonspecific and difficult to differentiate from bacterial cerebral abscesses. In reviewed cases, 55% of blood cultures and 23% of cerebrospinal fluid (CSF) cultures were positive for Candida spp. and outcomes were poor, as the mortality rate of the non-autopsy cases reviewed was 69%.

Purpose: In leukemic cutaneous T-cell lymphoma (L-CTCL), malignant T cells accumulate in the blood and give rise to widespread skin inflammation. Patients have intense pruritus, increased immunoglobulin E (IgE), and decreased T-helper (TH)-1 responses, and most die from infection. Depleting malignant T cells while preserving normal immunity is a clinical challenge. L-CTCL has been variably described as a malignancy of regulatory, TH2 and TH17 cells., Experimental Design: We analyzed phenotype and cytokine production in malignant and benign L-CTCL T cells, characterized the effects of malignant T cells on healthy T cells, and studied the immunomodulatory effects of treatment modalities in patients with L-CTCL., Results: Twelve out of 12 patients with L-CTCL overproduced TH2 cytokines. Remaining benign T cells were also strongly TH2 biased, suggesting a global TH2 skewing of the T-cell repertoire. Culture of benign T cells away from the malignant clone reduced TH2 and enhanced TH1 responses, but separate culture had no effect on malignant T cells. Coculture of healthy T cells with L-CTCL T cells reduced IFNγ production and neutralizing antibodies to interleukin (IL)-4 and IL-13 restored TH1 responses. In patients, enhanced TH1 responses were observed following a variety of treatment modalities that reduced malignant T-cell burden., Conclusions: A global TH2 bias exists in both benign and malignant T cells in L-CTCL and may underlie the infectious susceptibility of patients. TH2 cytokines from malignant cells strongly inhibited TH1 responses. Our results suggest that therapies that inhibit TH2 cytokine activity, by virtue of their ability to improve TH1 responses, may have the potential to enhance both anticancer and antipathogen responses.

Transient receptor potential (TRP) subfamily M member 5 (TRPM5) cation channel is involved in sensing sweet, bitter, umami, and fat taste stimuli, complex-tasting divalent salts, and temperature-induced changes in sweet taste. To investigate if the amiloride- and benzamil (Bz)-insensitive NaCl chorda tympani (CT) taste nerve response is also regulated in part by TRPM5, CT responses to 100 mM NaCl + 5 μM Bz (NaCl + Bz) were monitored in Sprague-Dawley rats, wild-type (WT) mice, and TRP vanilloid subfamily member 1 (TRPV1) and TRPM5 knockout (KO) mice in the presence of resiniferatoxin (RTX), a TRPV1 agonist. In rats, NaCl + Bz + RTX CT responses were also monitored in the presence of triphenylphosphine oxide, a specific TRPM5 blocker, and capsazepine and N-(3-methoxyphenyl)-4-chlorocinnamid (SB-366791), specific TRPV1 blockers. In rats and WT mice, RTX produced biphasic effects on the NaCl + Bz CT response, enhancing the response at 0.5-1 μM and inhibiting it at >1 μM. The NaCl + Bz + SB-366791 CT response in rats and WT mice and the NaCl + Bz CT response in TRPV1 KO mice were inhibited to baseline level and were RTX-insensitive. In rats, blocking TRPV1 by capsazepine or TRPM5 by triphenylphosphine oxide inhibited the tonic NaCl + Bz CT response and shifted the relationship between RTX concentration and the magnitude of the tonic CT response to higher RTX concentrations. TRPM5 KO mice elicited no constitutive NaCl + Bz tonic CT response. The relationship between RTX concentration and the magnitude of the tonic NaCl + Bz CT response was significantly attenuated and shifted to higher RTX concentrations. The results suggest that pharmacological or genetic alteration of TRPM5 activity modulates the Bz-insensitive NaCl CT response and its modulation by TRPV1 agonists.

Background: The use of many of the standard skin-directed mycosis fungoides (MF) therapies on facial skin may be limited by site-specific increased risks of side effects, excessive inflammation, and ocular toxicity., Objective: Our study aimed to describe the levels of erythema, scale, and induration of facial lesions in MF before and after low-dose high-dose-rate surface applicator brachytherapy and to examine the overall clinical response to brachytherapy., Methods: A total of 23 facial MF lesions in 10 patients were treated with high-dose-rate brachytherapy doses of 4 Gy per session for a total of 2 fractions at our multidisciplinary cutaneous oncology clinic between August 17, 2009, and March 12, 2012., Results: In all 23 lesions, dramatic clinical improvement was observed. Patients were followed up for a median of 6.3 months. No recurrences were reported in the follow-up period., Limitations: Long-term follow-up is lacking. Reassessment of all included patients at annual intervals for a period of at least 5 years is the authors' goal., Conclusion: Low-dose high-dose-rate brachytherapy using custom-made surface molds is a highly efficacious therapy in the treatment of facial lesions in MF., (Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Rothia mucilaginosa is increasingly recognized as an emerging opportunistic pathogen associated with prosthetic device infections. Infective endocarditis is one of the most common clinical presentations. We report a case of R. mucilaginosa prosthetic valve endocarditis and review the literature of prosthetic device infections caused by this organism.

Effects of N-geranyl cyclopropyl-carboxamide (NGCC) and four structurally related compounds (N-cyclopropyl E2,Z6-nonadienamide, N-geranyl isobutanamide, N-geranyl 2-methylbutanamide, and allyl N-geranyl carbamate) were evaluated on the chorda tympani (CT) nerve response to NaCl and monosodium glutamate (MSG) in rats and wild-type (WT) and TRPV1 knockout (KO) mice and on human salty and umami taste intensity. NGCC enhanced the rat CT response to 100 mM NaCl + 5 μM benzamil (Bz; an epithelial Na(+) channel blocker) between 1 and 2.5 μM and inhibited it above 5 μM. N-(3-methoxyphenyl)-4-chlorocinnamid (SB-366791, a TRPV1t blocker) inhibited the NaCl+Bz CT response in the absence and presence of NGCC. Unlike the WT mice, no NaCl+Bz CT response was observed in TRPV1 KO mice in the absence or presence of NGCC. NGCC enhanced human salt taste intensity of fish soup stock containing 60 mM NaCl at 5 and 10 μM and decreased it at 25 μM. Rat CT responses to NaCl+Bz and human salt sensory perception were not affected by the above four structurally related compounds. Above 10 μM, NGCC increased the CT response to MSG+Bz+SB-366791 and maximally enhanced the response between 40 and 60 μM. Increasing taste cell Ca(2+) inhibited the NGCC-induced increase but not the inosine monophosphate-induced increase in glutamate response. Addition of 45 μM NGCC to chicken broth containing 60 mM sodium enhanced the human umami taste intensity. Thus, depending upon its concentration, NGCC modulates salt taste by interacting with the putative TRPV1t-dependent salt taste receptor and umami taste by interacting with a Ca(2+)-dependent transduction pathway.

This article is based on proceedings from the Symposium on Sodium in the Food Supply: Challenges and Opportunities, sponsored by the North American Branch of the International Life Sciences Institute, at Experimental Biology 2010 in Anaheim, California. The symposium aimed to address the issue of dietary sodium and its consequences for public health. Presenters spoke on a variety of key topics, including salt taste reception mechanisms and preferences, methods and measures to assess sodium in the US food supply, and considerations regarding the reduction of sodium in processed foods. Information from these presentations, as well as literature references, are provided in this article., (© 2013 International Life Sciences Institute.)

The relationship between taste receptor cell (TRC) Ca(2+) concentration ([Ca(2+)](i)) and rat chorda tympani (CT) nerve responses to salty [NaCl and NaCl+benzamil (Bz)] and sour (HCl, CO(2), and acetic acid) taste stimuli was investigated before and after lingual application of ionomycin+Ca(2+), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM), U73122 (phospholipase C blocker), and thapsigargin (Ca(2+)-ATPase inhibitor) under open-circuit or lingual voltage-clamp conditions. An increase in TRC [Ca(2+)](i) attenuated the tonic Bz-sensitive NaCl CT response and the apical membrane Na(+) conductance. A decrease in TRC [Ca(2+)](i) enhanced the tonic Bz-sensitive and Bz-insensitive NaCl CT responses and apical membrane Na(+) conductance but did not affect CT responses to KCl or NH(4)Cl. An increase in TRC [Ca(2+)](i) did not alter the phasic response but attenuated the tonic CT response to acidic stimuli. A decrease in [Ca(2+)](i) did not alter the phasic response but attenuated the tonic CT response to acidic stimuli. In a subset of TRCs, a positive relationship between [H(+)](i) and [Ca(2+)](i) was obtained using in vitro imaging techniques. U73122 inhibited the tonic CT responses to NaCl, and thapsigargin inhibited the tonic CT responses to salty and sour stimuli. The results suggest that salty and sour taste qualities are transduced by [Ca(2+)](i)-dependent and [Ca(2+)](i)-independent mechanisms. Changes in TRC [Ca(2+)](i) in a BAPTA-sensitive cytosolic compartment regulate ion channels and cotransporters involved in the salty and sour taste transduction mechanisms and in neural adaptation. Changes in TRC [Ca(2+)](i) in a separate subcompartment, sensitive to inositol trisphosphate and thapsigargin but inaccessible to BAPTA, are associated with neurotransmitter release.

The relationship between taste receptor cell (TRC) intracellular Ca(2+) ([Ca(2+)](i)) and rat chorda tympani (CT) nerve responses to bitter (quinine and denatonium), sweet (sucrose, glycine, and erythritol), and umami [monosodium glutamate (MSG) and MSG + inosine 5'-monophosphate (IMP)] taste stimuli was investigated before and after lingual application of ionomycin (Ca(2+) ionophore) + Ca(2+), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM; Ca(2+) chelator), U73122 (phospholipase C blocker), thapsigargin (Ca(2+)-ATPase blocker), and diC8-PIP(2) (synthetic phosphatidylinositol 4,5-bisphosphate). The phasic CT response to quinine was indifferent to changes in [Ca(2+)](i). However, a decrease in [Ca(2+)](i) inhibited the tonic part of the CT response to quinine. The CT responses to sweet and umami stimuli were indifferent to changes in TRC [Ca(2+)](i). However, a decrease in [Ca(2+)](i) attenuated the synergistic effects of ethanol on the CT response to sweet stimuli and of IMP on the glutamate CT response. U73122 and thapsigargin inhibited the phasic and tonic CT responses to bitter, sweet, and umami stimuli. Although diC8-PIP(2) increased the CT response to bitter and sweet stimuli, it did not alter the CT response to glutamate but did inhibit the synergistic effect of IMP on the glutamate response. The results suggest that bitter, sweet, and umami taste qualities are transduced by [Ca(2+)](i)-dependent and [Ca(2+)](i)-independent mechanisms. Changes in TRC [Ca(2+)](i) in the BAPTA-sensitive cytosolic compartment regulate quality-specific taste receptors and ion channels that are involved in the neural adaptation and mixture interactions. Changes in TRC [Ca(2+)](i) in a separate subcompartment, sensitive to inositol trisphosphate and thapsigargin but inaccessible to BAPTA and ionomycin + Ca(2+), are associated with neurotransmitter release.

Weeksella virosa is an aerobic Gram-negative rod that has rarely been reported to cause infection. We describe a fatal case of W. virosa sepsis in a young female with end-stage renal disease, report three additional cases of W. virosa infection, and review the literature regarding this infection.

Background: Each year at least one million children worldwide die of pneumococcal infections. The development of bacterial resistance to antimicrobials adds to the difficulty of treatment of diseases and emphasizes the need for a preventive approach. Newborn vaccination schedules could substantially reduce the impact of pneumococcal disease in immunized children, but does not have an effect on the morbidity and mortality of infants less than three months of age. Pneumococcal vaccination during pregnancy may be a way of preventing pneumococcal disease during the first months of life before the pneumococcal vaccine administered to the infant starts to produce protection., Objectives: To assess the effect of pneumococcal vaccination during pregnancy for preventing infant infection., Search Methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 December 2011) and reference lists of retrieved studies., Selection Criteria: Randomized controlled trials in pregnant women comparing pneumococcal vaccine with placebo or doing nothing or with another vaccine to prevent infant infections., Data Collection and Analysis: Two review authors independently assessed trials for inclusion, methodological quality and extracted data using a data collection form. Data were checked for accuracy. We contacted study authors for additional information., Main Results: Seven trials were included, but only five trials (579 participants) contributed data. There was no evidence that pneumococcal vaccination during pregnancy reduces the risk of neonatal infection (risk ratio (RR) 0.66; 95% confidence interval (CI) 0.30 to 1.46; two trials, 241 pregnancies). Although the data suggest an effect in reducing pneumococcal colonization in infants by 16 months of age (RR 0.33; 95% CI 0.11 to 0.98; one trial, 56 pregnancies), there was no evidence of this effect in infants at two to three months of age (RR 1.13; 95% CI 0.46 to 2.78; two trials, 146 pregnancies) or by six to seven months of age (RR 0.66; 95% CI 0.20 to 2.17; two trials, 144 pregnancies). No significant difference for tenderness at the injection site between women who received pneumococcal vaccine and those who received control vaccine (RR 3.20; 95% CI 0.32 to 31.54; two trials, 130 women)., Authors' Conclusions: There is insufficient evidence to assess whether pneumococcal vaccination during pregnancy could reduce infant infections.

Strain differences between naive, sucrose- and ethanol-exposed alcohol-preferring (P) and alcohol-nonpreferring (NP) rats were investigated in their consumption of ethanol, sucrose, and NaCl; chorda tympani (CT) nerve responses to sweet and salty stimuli; and gene expression in the anterior tongue of T1R3 and TRPV1/TRPV1t. Preference for 5% ethanol and 10% sucrose, CT responses to sweet stimuli, and T1R3 expression were greater in naive P rats than NP rats. The enhancement of the CT response to 0.5 M sucrose in the presence of varying ethanol concentrations (0.5-40%) in naive P rats was higher and shifted to lower ethanol concentrations than NP rats. Chronic ingestion of 5% sucrose or 5% ethanol decreased T1R3 mRNA in NP and P rats. Naive P rats also demonstrated bigger CT responses to NaCl+benzamil and greater TRPV1/TRPV1t expression. TRPV1t agonists produced biphasic effects on NaCl+benzamil CT responses, enhancing the response at low concentrations and inhibiting it at high concentrations. The concentration of a TRPV1/TRPV1t agonist (Maillard reacted peptides conjugated with galacturonic acid) that produced a maximum enhancement in the NaCl+benzamil CT response induced a decrease in NaCl intake and preference in P rats. In naive P rats and NP rats exposed to 5% ethanol in a no-choice paradigm, the biphasic TRPV1t agonist vs. NaCl+benzamil CT response profiles were higher and shifted to lower agonist concentrations than in naive NP rats. TRPV1/TRPV1t mRNA expression increased in NP rats but not in P rats exposed to 5% ethanol in a no-choice paradigm. We conclude that P and NP rats differ in T1R3 and TRPV1/TRPV1t expression and neural and behavioral responses to sweet and salty stimuli and to chronic sucrose and ethanol exposure.

The relationship between acidic pH, taste cell pH(i), and chorda tympani (CT) nerve responses was investigated before and after incorporating the K(+)-H(+) exchanger, nigericin, in the apical membrane of taste cells. CT responses were recorded in anesthetized rats in vivo, and changes in pH(i) were monitored in polarized fungiform taste cells in vitro. Under control conditions, stimulating the tongue with 0.15 M potassium phosphate (KP) or 0.15 M sodium phosphate (NaP) buffers of pHs between 8.0 and 4.6, KP or NaP buffers did not elicit a CT response. Post-nigericin (500 × 10(-6) M), KP buffers, but not NaP buffers, induced CT responses at pHs ≤ 6.6. The effect of nigericin was reversed by the topical lingual application of carbonyl cyanide 3-chloro-phenylhydrazone, a protonophore. Post-nigericin (150 × 10(-6) M), KP buffers induced a greater decrease in taste cell pH(i) relative to NaP buffers and to NaP and KP buffers under control conditions. A decrease in pH(i) to about 6.9 induced by KP buffers was sufficient to elicit a CT response. The results suggest that facilitating apical H(+) entry via nigericin decreases taste cell pH(i) and demonstrates directly a strong correlation between pH(i) and the magnitude of the CT response.

To investigate if chorda tympani (CT) taste nerve responses to strong (HCl) and weak (CO(2) and acetic acid) acidic stimuli are dependent upon NADPH oxidase-linked and cAMP-sensitive proton conductances in taste cell membranes, CT responses were monitored in rats, wild-type (WT) mice, and gp91(phox) knockout (KO) mice in the absence and presence of blockers (Zn(2+) and diethyl pyrocarbonate [DEPC]) or activators (8-(4-chlorophenylthio)-cAMP; 8-CPT-cAMP) of proton channels and activators of the NADPH oxidase enzyme (phorbol 12-myristate 13-acetate [PMA], H(2)O(2), and nitrazepam). Zn(2+) and DEPC inhibited and 8-CPT-cAMP, PMA, H(2)O(2), and nitrazepam enhanced the tonic CT responses to HCl without altering responses to CO(2) and acetic acid. In KO mice, the tonic HCl CT response was reduced by 64% relative to WT mice. The residual CT response was insensitive to H(2)O(2) but was blocked by Zn(2+). Its magnitude was further enhanced by 8-CPT-cAMP treatment, and the enhancement was blocked by 8-CPT-adenosine-3'-5'-cyclic monophospho-rothioate, a protein kinase A (PKA) inhibitor. Under voltage-clamp conditions, before cAMP treatment, rat tonic HCl CT responses demonstrated voltage-dependence only at ±90 mV, suggesting the presence of H(+) channels with voltage-dependent conductances. After cAMP treatment, the tonic HCl CT response had a quasi-linear dependence on voltage, suggesting that the cAMP-dependent part of the HCl CT response has a quasi-linear voltage dependence between +60 and -60 mV, only becoming sigmoidal when approaching +90 and -90 mV. The results suggest that CT responses to HCl involve 2 proton entry pathways, an NADPH oxidase-dependent proton channel, and a cAMP-PKA sensitive proton channel.

Regulation of the putative amiloride and benzamil (Bz)-insensitive TRPV1t salt taste receptor by phosphatidylinositol 4,5-bisphosphate (PIP(2)) was studied by monitoring chorda tympani (CT) taste nerve responses to 0.1 M NaCl solutions containing Bz (5 x 10(-6) M; a specific ENaC blocker) and resiniferatoxin (RTX; 0-10 x 10(-6) M; a specific TRPV1 agonist) in Sprague-Dawley rats and in wildtype (WT) and TRPV1 knockout (KO) mice. In rats and WT mice, RTX elicited a biphasic effect on the NaCl + Bz CT response, increasing the CT response between 0.25 x 10(-6) and 1 x 10(-6) M. At concentrations >1 x 10(-6) M, RTX inhibited the CT response. An increase in PIP(2) by topical lingual application of U73122 (a phospholipase C blocker) or diC8-PIP(2) (a short chain synthetic PIP(2)) inhibited the control NaCl + Bz CT response and decreased its sensitivity to RTX. A decrease in PIP(2) by topical lingual application of phenylarsine oxide (a phosphoinositide 4 kinase blocker) enhanced the control NaCl + Bz CT response, increased its sensitivity to RTX stimulation, and inhibited the desensitization of the CT response at RTX concentrations >1 x 10(-6) M. The ENaC-dependent NaCl CT responses were not altered by changes in PIP(2). An increase in PIP(2) enhanced CT responses to sweet (0.3 M sucrose) and bitter (0.01 M quinine) stimuli. RTX produced the same increase in the Bz-insensitive Na(+) response when present in salt solutions containing 0.1 M NaCl + Bz, 0.1 M monosodium glutamate + Bz, 0.1 M NaCl + Bz + 0.005 M SC45647, or 0.1 M NaCl + Bz + 0.01 M quinine. No effect of RTX was observed on CT responses in WT mice and rats in the presence of the TRPV1 blocker N-(3-methoxyphenyl)-4-chlorocinnamide (1 x 10(-6) M) or in TRPV1 KO mice. We conclude that PIP(2) is a common intracellular effector for sweet, bitter, umami, and TRPV1t-dependent salt taste, although in the last case, PIP(2) seems to directly regulate the taste receptor protein itself, i.e., the TRPV1 ion channel or its taste receptor variant, TRPV1t.